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Biomedical subjects

J R Taylor

Publications and source records attributed to J R Taylor.

At least 55 records · Page 3Linked to original sources
PubMed2000

Pathogenesis of primary R5 human immunodeficiency virus type 1 clones in SCID-hu mice.

We studied the replication and cytopathicity in SCID-hu mice of R5 human immunodeficiency virus type 1 (HIV-1) biological clones from early and late stages of infection of three patients who never developed MT-2 cell syncytium-inducing (SI; R5X4 or X4) viruses. Several of the late-stage non-MT-2 cell syncytium-inducing (NSI; R5) viruses from these patients depleted human CD4(+) thymocytes from SCID-hu mice. Earlier clones from the same patients did not deplete CD4(+) thymocytes from SCID-hu mice as well as later clones. We studied three R5 HIV-1 clones from patient ACH142 in greater detail. Two of these clones were obtained prior to the onset of AIDS; the third was obtained following the AIDS diagnosis. In GHOST cell infection assays, all three ACH142 R5 HIV-1 clones could infect GHOST cells expressing CCR5 but not GHOST cells expressing any of nine other HIV coreceptors tested. Furthermore, these patient clones efficiently infected stimulated peripheral blood mononuclear cells from a normal donor but not those from a homozygous CCR5Delta32 individual. Statistical analyses of data obtained from infection of SCID-hu mice with patient ACH142 R5 clones revealed that only the AIDS-associated clone significantly depleted CD4(+) thymocytes from SCID-hu mice. This clone also replicated to higher levels in SCID-hu mice than the two earlier clones, and a significant correlation between viral replication and CD4(+) thymocyte depletion was observed. Our results indicate that an intrinsic property of AIDS-associated R5 patient clones causes their increased replication and cytopathic effects in SCID-hu mice and likely contributes to the development of AIDS in patients who harbor only R5 quasispecies of HIV-1.

Animals↗
PubMed2000

Thebesian sinusoids: forgotten collaterals to papillary muscles.

BACKGROUND: Papillary muscles of the left ventricle are prone to ischemic damage but seldom rupture, perhaps because they are protected by transendocardial diffusion and thebesian sinusoids as well as by arteries. Sinusoids are primitive vessels that precede coronary arteries as nutrient suppliers to all parts of the embryonic heart. OBJECTIVES: To determine whether sinusoids penetrate to the tips of papillary muscles. MATERIALS AND METHODS: Adult hearts with and without evidence of acute and chronic ischemic lesions were selected. Papillary muscle sinusoids were perfused by black ink from the apex of the left ventricle. Papillary muscles and the adjacent ventricular free walls were then excised and fixed before gross and microscopic examination for inked sinusoids. Some fixed specimens were cleared through methyl salicylate and examined stereoscopically. RESULTS: The meshwork of trabeculae and, importantly, intertrabecular spaces lining the apex of the left ventricle continue into the deeply undercut bases of papillary muscles. In most hearts, sinusoids can be shown to extend from the undercut bases to the tips of human papillary muscles, especially in ischemic hearts. The compact myocardium of the adjacent ventricular free wall contains few sinusoids. CONCLUSIONS: Sinusoids may supplement normal arterial flow to papillary muscles and mitigate the effects of coronary occlusion. The authors hypothesize that the apex of the human left ventricle is adapted for sinusoidal flow to papillary muscles.

Adult↗
PubMed1999

A role for norepinephrine in stress-induced cognitive deficits: alpha-1-adrenoceptor mediation in the prefrontal cortex.

BACKGROUND: Stress exacerbates many neuropsychiatric disorders associated with prefrontal cortical (PFC) dysfunction. Stress also impairs the working memory functions of the PFC. Although stress research has focused on dopaminergic mechanisms, stress also increases norepinephrine (NE) release in PFC, and intra-PFC infusions of NE alpha-1-adrenoceptor agonists impair working memory. The current study examined whether NE alpha-1-adrenoceptor actions in PFC contribute to stress-induced deficits in working memory performance. METHODS: Rats were treated with a pharmacological stressor, FG7142 (30 mg/kg) or vehicle 30 min before testing on a test of spatial working memory, delayed alternation. The alpha-1-adrenoceptor antagonist, urapidil (0.1 microgram/0.5 microL), or saline vehicle, was infused into the PFC 15 min before delayed alternation testing. RESULTS: As observed previously, FG7142 significantly impaired the accuracy of delayed alternation performance, and induced a perseverative pattern of responding consistent with PFC dysfunction. FG7142 also slowed motor response times. Infusion of urapidil into the PFC completely reversed the FG7142-induced impairment in delayed alternation performance, but did not alter the slowed motor responding. CONCLUSIONS: These findings indicate that alpha-1-adrenoceptor stimulation in the PFC contributes to stress-induced impairments in PFC cognitive functions. These neurochemical actions may contribute to symptoms of working memory impairment, poor attention regulation, or disinhibited behaviors in neuropsychiatric disorders sensitive to stress exposure.

Adrenergic alpha-Antagonists↗
PubMed1999

Activation of cAMP-dependent protein kinase A in prefrontal cortex impairs working memory performance.

Activation of the adenylyl cyclase-cAMP-protein kinase A (PKA) intracellular signaling cascade is necessary for long-term memory consolidation in brain regions such as the hippocampus. However, the role of the PKA cascade in the working memory functions of the prefrontal cortex (PFC) is unknown. The present study examined the effects of manipulating PKA activity in the PFC using the cAMP stereoisomers Sp-cAMPS and Rp-cAMPS, which activate and inhibit PKA, respectively. Animals received bilateral infusions of Sp-cAMPS and/or Rp-cAMPS into the PFC immediately before testing on the delayed alternation task, a test of spatial working memory that depends on the integrity of the PFC. Low doses of Sp-cAMPS (0.21, 2. 1, or 21 nmol/0.5 microl) produced a marked, dose-dependent impairment in working memory performance. The impairment produced by infusion of Sp-cAMPS (21 nmol/0.5 microl) was fully reversed by co-infusion of Rp-cAMPS (21 nmol/0.5 microl), consistent with actions on PKA. Rp-cAMPS (21 or 42 nmol/0.5 microl) by itself had no effect on performance. These results indicate that activation of the PKA intracellular signaling cascade in the PFC impairs working memory performance. The current findings contrast with studies of long-term memory consolidation, in which inhibition of PKA with agents such as Rp-cAMPS impaired memory consolidation (Bernabeu et al., 1997; Bourtchouladze et al., 1998), whereas enhancement of the PKA pathway improved memory (Bernabeu et al., 1997; Barad et al., 1998). These results demonstrate that discrete cognitive processes subserved by different cortical regions are mediated by distinct intracellular mechanisms.

Animals↗
PubMed1999

Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor.

The mesolimbic dopamine (DA) system has been implicated in drug reward, locomotor sensitization, and responding for reward-related stimuli [termed conditioned reinforcers (CR)]. Here, we investigated the effect of brain-derived neurotrophic factor (BDNF), which enhances the survival and function of dopaminergic neurons, on stimulant-induced locomotor sensitization and responding for CR. In experiment 1, BDNF was infused into the nucleus accumbens (NAc) or ventral tegmental area over 2 weeks via chronically implanted minipumps (1-2.5 microgram/d), and the psychomotor stimulant effects of cocaine (5-15 mg/kg, i.p.) were studied. We found that BDNF enhanced the initial stimulant effects of cocaine and seemed to facilitate the development of sensitization to repeated cocaine doses. In experiment 2, we studied the effects of intra-NAc BDNF infusions on responding for CR. BDNF-treated rats showed twice as many CR responses compared with controls when saline was first administered. BDNF enhanced responding on the CR lever more than four times that seen in control animals after a cocaine injection (10 mg/kg, i.p.). The enhanced response to cocaine in BDNF-treated animals persisted for more than a month after the BDNF infusions had stopped, indicating long-lasting changes in the mesolimbic DA system caused by BDNF administration. In experiment 3, we examined locomotor sensitization to cocaine in heterozygous BDNF knock-out mice and found that the development of sensitization was delayed compared with wild-type littermates. These results demonstrate the profound effects of BDNF on the enhancement of both cocaine-induced locomotion and facilitation of CR and suggest a possible role for BDNF in long-term adaptations of the brain to cocaine.

Animals↗
PubMed1999

Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function.

BACKGROUND: Many neuropsychiatric disorders are associated with high levels of noradrenergic turnover, and most antipsychotic medications have alpha-1 adrenoceptor blocking properties, yet little is known about alpha-1 influences on higher cortical function. METHODS: The alpha-1 adrenergic agonist, phenylephrine, was infused into the prefrontal cortex (PFC) of rats (0.1 microgram/0.5 microL) performing a spatial working memory task, delayed alternation. The phenylephrine response was challenged with coinfusion of the alpha-1 adrenergic antagonist, uripidil (0.01 microgram), or with a dose of lithium chloride (4 mEq/kg, i.p., 18 hours) known to suppress phosphotidylinositol (PI) turnover, the second messenger pathway coupled to alpha-1 adrenoceptors. RESULTS: Phenylephrine infusions in PFC markedly impaired delayed alternation performance. The phenylephrine response was reversed by coinfusion of uripidil, or by pretreatment with lithium, consistent with actions at alpha-1 adrenoceptors coupled to a PI pathway. CONCLUSIONS: These findings demonstrate that alpha-1 adrenoceptor stimulation in the PFC impairs cognitive function. Excessive stimulation of alpha-1 adrenoceptors may contribute to PFC deficits (e.g., distractibility, impulsivity) in disorders such as mania, dementia, and anxiety associated with high noradrenergic turnover.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1999

Spontaneous blink rates correlate with dopamine levels in the caudate nucleus of MPTP-treated monkeys.

Previous studies have suggested a dopaminergic regulation of eye blink rates in human and nonhuman primates. Blockade of either dopamine (DA) D1 or DA D2 receptors or DA depletion induced by the dopaminergic neurotoxin MPTP both decrease spontaneous eye blink rates in monkeys. MPTP-induced decreases in blink rates can be reversed by administration of the full efficacy D1 agonist dihydrexidine, which has also been found to have dramatic antiparkinsonian effects in MPTP-treated animals. Increases in blink rates can also be induced by D1 and D2 agonists in normal animals. In the current study, we have investigated whether blink rates correlate with concentrations of DA or HVA and/or HVA:DA ratios in specific brain regions in MPTP-treated monkeys. Furthermore, the potential relationship between the severity of behavioral indices of parkinsonism and blink rates were examined. We found that (1) blink rates significantly correlate positively with concentration of DA and inversely with HVA:DA ratios in the rostral portion of the ventromedial body of the caudate nucleus (CD), but not other subcortical regions, and (2) that severity of parkinsonism was inversely correlated with blink rate. These data support a dopaminergic regulation of blink rate and suggest that the ventromedial region of the body of the CD may be critically involved in regulation of blink rate.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli.

Drug abuse and dependence define behavioral states involving increased allocation of behavior towards drug seeking and taking at the expense of more appropriate behavioral patterns. As such, addiction can be viewed as increased control of behavior by the desired drug (due to its unconditioned, rewarding properties). It is also clear that drug-associated (conditioned) stimuli acquire heightened abilities to control behaviors. These phenomena have been linked with dopamine function within the ventral striatum and amygdala and have been described specifically in terms of motivational and incentive learning processes. New data are emerging that suggest that regions of the frontal cortex involved in inhibitory response control are directly affected by long-term exposure to drugs of abuse. The result of chronic drug use may be frontal cortical cognitive dysfunction, resulting in an inability to inhibit inappropriate unconditioned or conditioned responses elicited by drugs, by related stimuli or by internal drive states. Drug-seeking behavior may thus be due to two related phenomena: (1) augmented incentive motivational qualities of the drug and associated stimuli (due to limbic/amygdalar dysfunction) and (2) impaired inhibitory control (due to frontal cortical dysfunction). In this review, we consider the neuro-anatomical and neurochemical substrates subserving inhibitory control and motivational processes in the rodent and primate brain and their putative impact on drug seeking. The evidence for cognitive impulsivity in drug abuse associated with dysfunction of the frontostriatal system will be discussed, and an integrative hypothesis for compulsive reward-seeking in drug abuse will be presented.

Animals↗
PubMed1999

Enhanced responding for conditioned reward produced by intra-accumbens amphetamine is potentiated after cocaine sensitization.

The mesolimbic dopamine (DA) system has been implicated in conditioned reward (CR), locomotor sensitization, and the reinforcing properties of psychomotor stimulants. Stimuli with formerly motivationally neutral properties that gain incentive properties by their predictive association with primary reinforcers are termed conditioned, or secondary, reinforcers. In these experiments, we investigated whether cocaine sensitization could potentiate augmented responding for CR produced by intra-accumbens amphetamine. After subjects were trained on the CR paradigm for 14 days, they received a regimen of cocaine sensitization or saline injections. On 2 test days, 8-10 days later, subjects were given amphetamine (6 microg/0.5 microl) or saline infusions into the nucleus accumbens (NAc) and responding for CR was measured using the "acquisition of a new response" paradigm. Responding on one novel lever resulted in the delivery of the conditioned stimulus (conditioned reinforcer, or CR lever), whereas responding on the other lever resulted in no CR stimulus presentation (NCR lever). Animals sensitized to cocaine showed increased responding on the CR lever after intra-NAc saline and potentiated CR lever responding after intra-NAc amphetamine. No differences in responding between the cocaine- and saline-treated groups on the NCR lever after the challenge were found. Locomotor sensitization under these conditions was confirmed in a separate group of subjects. These findings show that prior exposures to cocaine results in changes that potentiate the ability of intra-NAc amphetamine to enhance CR. Repeated stimulant drug use may induce long-term neuronal adaptations that result in increased sensitivity to the behavioral, or incentive motivational, effects of stimulant drugs.

Amphetamine↗
PubMed1999

Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys.

D4 dopamine receptors (DRs) are enriched in the primate prefrontal cortex, a brain region implicated in cognitive processes, and mesoprefrontal dopaminergic systems appear to be involved in modulating some cognitive functions of the prefrontal cortex. Despite anatomical localization of D4 DRs within the frontal cortex, the role of these receptors, specifically, in the regulation of cognition or behavior in primates is unknown. In these studies, we sought to learn whether specific antagonism of D4 DRs would affect performance of a task dependent on the frontostriatal system. The effects of NGD94-1 (2-phenyl-4(5)-[4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazol e dimaleate), a potent and selective D4 DR antagonist and haloperidol, a non-specific D2-like DR antagonist, on the performance of an object retrieval/detour task by monkeys were examined. The effects of these antagonists on the object retrieval task were evaluated in normal control monkeys and in subjects repeatedly exposed to phencyclidine (PCP), to induce frontal cortical dopaminergic and cognitive dysfunction. NGD94-1 (1-5 mg/kg) reversed the cognitive deficits of PCP pre-treated monkeys, whereas haloperidol (25 microg/kg) exacerbated PCP-induced performance impairments. A low dose of NGD94-1 failed to affect performance of control subjects, while both haloperidol and a high dose of NGD94-1 impaired control performance. These data show, for the first time, that D4 DRs modulate the cognitive functions of the frontostriatal system.

Animals↗
PubMed1999

Altered frontal cortical dopaminergic transmission in monkeys after subchronic phencyclidine exposure: involvement in frontostriatal cognitive deficits.

Long-term exposure to the psychotomimetic drug phencyclidine produces prefrontal cortical cognitive and dopaminergic dysfunction in rats and monkeys, effects possibly relevant to the frontal cortical impairments of schizophrenia. In the present study, the effects of subchronic phencyclidine administration (0.3 mg/kg twice-daily for 14 days) on monoamine systems in the monkey brain were examined and related to cognitive performance on an object retrieval/detour task, which has been linked with frontostriatal function. Long-term (14 days) administration of phencyclidine resulted in a marked and persistent reduction in dopamine utilization in the frontal cortex. Moreover, the degree of cognitive impairment in phencyclidine-treated monkeys correlated significantly with the magnitude of dopaminergic inhibition within the dorsolateral prefrontal cortex and prelimbic cortex. No specific correlation was measured for dopamine utilization in other cortical regions or for indices of serotonin transmission in any brain region. These data show that repeated exposure to phencyclidine reduces prefrontal cortical dopamine transmission, and this inhibition of dopaminergic function is associated with performance impairments on a task sensitive to frontostriatal cognitive dysfunction. Thus, the cognitive deficits of phencyclidine-treated monkeys, as in schizophrenia, appear to be mediated, in part, by reduced dopaminergic function in specific subregions of the frontal cortex.

Animals↗
PubMed1999

The prepuce.

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Aging↗
PubMed1999

Does wound healing contribute to the eradication of basal cell carcinoma following curettage and electrodessication?

BACKGROUND: Histologic studies indicate that C&D fails to mechanically remove all the tumor in a percentage of cases that far exceeds the 5-year recurrence rate. This raises the question that if C&D does not mechanically remove the tumor in a significant number of patients, why don't we observe tumor recurrence in most of these patients? Our previous study indicates that inflammation occurring over 1 month following C&D does not clear residual tumor. It may be some other process, requiring more time, that clears the residual tumor. Perhaps the proliferative or maturation phase of wound healing or, alternatively, a slow-acting process such as a low-grade immune response set in motion earlier, clears the residual tumor. OBJECTIVE: To test the hypothesis that wound healing and maturation following C&D clear residual tumor that has not mechanically removed by the procedure. METHODS: The frequency of residual BCC detected histologically immediately following C&D was compared with the frequency 3 months after the C&D, an amount of time in which the maturation phase of wound healing is well under way. RESULTS: Twenty-two of 29 primary BCC less than 1 cm in size were tumor-free immediately following the procedure (clearance rate 75.9%). Twelve primary BCC <1 cm were treated by C&D, allowed to heal for 3 months, and then excised and checked histologically. Ten of the twelve BCC were free of tumor, for a clearance rate of 83.3%, which is not a statistically significant difference (p = 0.7187). CONCLUSION: By 3 months, the proliferative phase of wound healing is complete, and our study indicates that this phase has no effect on clearing the tumor. The maturation phase is well under way three months following C&D, and no statistically significant effect was observed.

Basal Cell Carcinoma↗
PubMed1999

Probable antagonism of warfarin by green tea.

OBJECTIVE: To report a case of the inhibition of the effect of warfarin by green tea. CASE SUMMARY: A 44-year-old white man was receiving warfarin for thromboembolic prophylaxis secondary to a St. Jude mechanical valve replacement in the aortic position. The patient had an international normalized ratio (INR) of 3.20 approximately one month prior to entering our clinic, and an INR of 3.79 on entering our clinic. Twenty-two days later his INR was 1.37. One month later the patient's INR was 1.14. It was subsequently discovered that the patient began drinking one-half to one gallon of green tea per day about one week prior to the INR of 1.37. On discontinuation of the green tea, the patient's INR increased to 2.55. DISCUSSION: Warfarin produces anticoagulation by inhibiting production of the vitamin K-dependent clotting factors (i.e., factors II, VII, IX, X). The exogenous administration of vitamin K inhibits the effect of warfarin and reduces a patient's degree of anticoagulation. Green tea can be a significant source of vitamin K and thus antagonize the effect of warfarin. CONCLUSIONS: Warfarin is a highly effective oral anticoagulant, but it requires close monitoring to prevent complications. Patients receiving warfarin need to be routinely questioned about their intake of vitamin K-containing foods and beverages.

Adult↗
PubMed1999

The thebesian circulation to developing conducting tissue: a nutrient-nodal hypothesis of cardiogenesis.

BACKGROUND: In a previous paper the authors suggested that the right atrial appendage is structured for retrograde sinusoidal blood flow to embryonic conducting tissue in the venous sinus portion of the right atrium. OBJECTIVE: To test the hypothesis that the relationship among conducting, valvar and trabecular myocardium of the human heart is primarily for the nutrition of the heart itself rather than for downstream blood flow. MATERIAL AND METHODS: Embryonic, fetal, infant and adult human hearts were studied grossly and microscopically for evidence of a dedicated sinusoidal blood supply to the atrioventricular node. Outflow tract anatomy was reviewed to test the hypothesis that junctional zones, nodal or non-nodal, are structured according to the same basic principle concerning nutrient supply to conducting tissue. CONCLUSIONS: The finding of a sinusoid-rich 'spongy trabecula' in relation to the septal node suggests that the septal junctional zone, like the sinoatrial junctional zone, is structured for retrograde sinusoidal blood flow to nodal conducting tissue. The anatomy of the pulmonary and aortic outflow tracts supports the idea that the heart is structured from repeating triplets of conducting, valvar and sinusoid-rich trabeculae. Although the heart is an external pump, it is structured as an internal pump.

Adult↗
PubMed1998

Upregulation of striatal D2 receptors in the MPTP-treated vervet monkey is reversed by grafts of fetal ventral mesencephalon: an autoradiographic study.

Although neural transplantation holds promise as a treatment for Parkinson's disease, parkinsonian primates have generally exhibited inconsistent and incomplete recovery of motor functions following intrastriatal grafting of fetal ventral mesencephalon. One possible contributing factor to this variable response is lack of appropriate integration of donor neurons with host striatal circuitry with the result that there is insufficient dopamine release and postsynaptic dopamine receptor activation. This issue was examined by measuring the effect of transplanting fetal ventral mesencephalon to the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated (MPTP) monkeys on striatal D2 receptor binding. One year after receiving MPTP, D2 receptor binding was upregulated in the dorsal and ventral striatum of African green monkeys. Grafting of fetal ventral mesencephalon to the dorsal striatum of MPTP-treated monkeys 9 months before sacrifice, eliminated the D2 receptor upregulation in dorsal, but not ventral, region. Dopamine concentration in dorsal striatum of grafted MPTP-treated monkeys was significantly higher than in that region of MPTP-treated non-grafted monkeys. In addition, dopamine concentration was significantly higher in dorsal compared to ventral striatum of grafted MPTP-treated monkeys. These data, in addition to those from a previous autoradiographic study on dopamine uptake site density in these monkeys, strongly supports the hypothesis that ectopically placed ventral mesencephalon not only produces, but maintains the release of sufficient levels of dopamine to restore postsynaptic dopamine transmission in regions influenced by graft-derived dopamine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Pattern of synaptophysin immunoreactivity within mesencephalic grafts following transplantation in a parkinsonian primate model.

The majority of investigations into the degree of restoration of neural circuitry following transplantation of the embryonic ventral mesencephalon to the striatum have focused upon the particular neurochemical subtypes of the fibers exchanged between graft and host. Visualization of neurites of specific neurotransmitter type while informative regarding the specificity of graft-host interactions, vastly underrepresents overall synaptogenesis as it may occur in the grafting situation. The present approach of using a molecular marker characteristic of all normal, functional synapses provides broader information about the synaptic remodeling that occurs after tissue grafting. Synaptophysin (SY), an integral membrane protein of the synaptic vesicle, is a reliable marker of nerve terminal differentiation. Immunohistochemical staining with antibodies directed against SY and the dopamine synthetic enzyme tyrosine hydroxylase (TH) was used to assess overall synaptic differentiation as well as the relationship between SY immunoreactivity and the distribution of grafted dopamine (DA) neurons and processes in mesencephalic grafts and mesencephalic-striatal co-grafts implanted in the striatum of MPTP-treated African green monkeys. Grafted embryonic cerebellar tissue was used as a comparison graft type that does not normally exchange prominent direct projections with striatum. Dense pericellular arrays of SY-positive terminals were associated with TH-positive neurons in mesencephalic grafts. In mixed mesencephalic-striatal co-grafts, TH-positive fiber patches within the striatal portion of the graft demonstrated a high degree of correspondence with SY immunoreactivity. In contrast, grafts of cerebellar tissue did not display the same pattern of prominent pericellular arrays of SY staining. These observations suggest that functional synapses are abundantly present within grafted mesencephalon, and that these contacts are enriched in areas of the graft occupied by DA neurons. Implantation of an inappropriate striatal target, the cerebellum, results in visibly diminished innervation. The pattern of SY labeling observed suggests that tissue grafts are extensively innervated, probably both from extrinsic and intrinsic sources, and that the pattern and density of this innervation corresponds to the appropriateness of the graft-host interaction.

Animals↗